Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric complication that occurs due to deteriorating hepatic function and this syndrome influences patient quality of life, clinical management strategies and survival. During acute liver failure, circulating bile acids increase due to a disruption of the enterohepatic circulation. We previously identified that bile acid-mediated signaling occurs in the brain during HE and contributes to cognitive impairment. However, the influences of bile acids and their downstream signaling pathways on HE-induced neuroinflammation have not been assessed. Conjugated bile acids, such as taurocholic acid (TCA), can activate sphingosine-1-phosphate receptor 2 (S1PR2), which has been shown to promote immune cell infiltration and inflammation in other models. The current study aimed to assess the role of bile-acid mediated S1PR2 signaling in neuroinflammation and disease progression during azoxymethane (AOM)-induced HE in mice. Our findings demonstrate a temporal increase of bile acids in the cortex during AOM-induced HE and identified that cortical bile acids were elevated as an early event in this model. In order to classify the specific bile acids that were elevated during HE, a metabolic screen was performed and this assay identified that TCA was increased in the serum and cortex during AOM-induced HE. To reduce bile acid concentrations in the brain, mice were fed a diet supplemented with cholestyramine, which alleviated neuroinflammation by reducing proinflammatory cytokine expression in the cortex compared to the control diet-fed AOM-treated mice. S1PR2 was expressed primarily in neurons and TCA treatment increased chemokine ligand 2 mRNA expression in these cells. The infusion of JTE-013, a S1PR2 antagonist, into the lateral ventricle prior to AOM injection protected against neurological decline and reduced neuroinflammation compared to DMSO-infused AOM-treated mice. Together, this identifies that reducing bile acid levels or S1PR2 signaling are potential therapeutic strategies for the management of HE.
Highlights
Hepatic encephalopathy (HE) is a neuropsychiatric complication that occurs due to deteriorating hepatic function and this syndrome influences patient quality of life, clinical management strategies and survival (Butterworth, 2011)
The mechanisms that lead to the activation of microglia during HE are not fully understood but we have shown that this can occur as a consequence of chemokine ligand 2 (CCL2) release from neurons acting on and activating microglia (McMillin et al, 2014a)
Levels of total cortical bile acids are increased as an early event during AOM-induced HE, with a significant increase beginning at a stage of minor neurological decline until coma when compared to vehicle-treated controls (Figure 1A)
Summary
Hepatic encephalopathy (HE) is a neuropsychiatric complication that occurs due to deteriorating hepatic function and this syndrome influences patient quality of life, clinical management strategies and survival (Butterworth, 2011). When microglia become activated in the brain, they begin producing proinflammatory cytokines and factors that promote oxidative stress (Voloboueva and Giffard, 2011) Due to both neuroinflammation and oxidative stress contributing to the pathogenesis of HE, it is not surprising that microglia activation has been observed during HE in animal models (Jiang et al, 2009a,b; Rodrigo et al, 2010; Chastre et al, 2012; Rangroo Thrane et al, 2012; Dadsetan et al, 2016; McMillin et al, 2016b) in patients with HE (Wright et al, 2007; Butterworth, 2011; Dennis et al, 2014), as well as in a rat model of hyperammonemia (Hernández-Rabaza et al, 2016). The identification of factors that lead to the release of CCL2, and the subsequent neuroinflammation and neurological decline that result, are yet to be identified
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